ZA200604046B - A2B Adenosine receptor antagonists - Google Patents

A2B Adenosine receptor antagonists Download PDF

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ZA200604046B
ZA200604046B ZA200604046A ZA200604046A ZA200604046B ZA 200604046 B ZA200604046 B ZA 200604046B ZA 200604046 A ZA200604046 A ZA 200604046A ZA 200604046 A ZA200604046 A ZA 200604046A ZA 200604046 B ZA200604046 B ZA 200604046B
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formula
compound
ethyl
contacting
propyl
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ZA200604046A
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Elzein Elfatih
Kalla Rao
Marquart Tim
Zablocki Jeff
Li Xiaofen
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Cv Therapeutics Inc
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    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
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Description

Aop ADENOSINE RECEPTOR ANTAGONISTS
Field of the Invention
The present invention relates to App adenosine receptor antagonists, and to their use in treating mammals for various disease states, such as gastrointestinal disorders, immunologicat disorders, neurological disorders, and cardiovascular diseases due to both cellular hyperproliferation and apoptosis, and the like. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
Background
Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors characterized as Ay, Aza,
Ap, and As, all of which modulate important physiological processes. For example,
A, adenosine receptors modulate coronary vasodilation, Az receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine Asp Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol
Sci 19:148-153), and A; adenosine receptors modulate cell proliferation processes.
Adenosine Ap receptors are ubiquitous, and regulate multiple biological activities. For example, adenosine binds to Azp receptors on endothelial cells, thereby stimulating angiogenesis. Adenosine also regulates the growth of smooth muscle cell populations in blood vessels. Adenosine stimulates Ap receptors on mast cells, thus modulating Type I hypersensitivity reactions. Adenosine also stimulates gastrosecretory activity by ligation with Ap in the intestine.
While many of these biological effects of adenosine are necessary to maintain normal tissue horneostasis, under certain physiological changes it is desirable to modulate its effects. For example, the binding of Asp receptors stimulates angiogenesis by promoting the growth of endothelial cells. Such activity is necessary in healing wounds, but the hyperproliferation of endothelial cells promotes diabetic retinopathy. Also, an undesirable increase in blood vessels occurs in neoplasia.
Accordingly, inhibition of the binding of adenosine to A,p receptors in the endothelium will alleviate or prevent hypervasculation, thus preventing retinopathy and inhibibiting tumor formation. :
Ap receptors are found in the colon in the basolateral domains of intestinal epithelial cells, and when acted upon by the appropriate ligand act to increase chloride secretion, thus causing diarrhea, which is a common and potentially fatal complication of infectious diseases such as cholera and typhus. As antagonists can therefore be used to block intestinal chloride secretion, and are thus useful in the treatment of inflammatory gastrointestinal tract disorders, including diarrhea.
Insensitivity to insulin exacerbates diabetes and obesity. Insulin sensitivity is decreased by the interaction of adenosine with Agp receptors. Thus, blocking the adenosine Asp receptors of individuals with diabetes or obesity would benefit patients with these disorders. It has also been demonstrated that A;p-antagonists cause a reduction of blood glucose levels, and thus would be particularly useful in the treatment of type-II diabetes.
Another adverse biological effect of adenosine acting at the Ap receptor is the over-stimulation of cerebral IL-6, a cytokine associated with dementias and
Altheimer’s disease. Inhibiting the binding of adenosine to A;p receptors would therefore mitigate those neurological disorders that are produced by IL-6.
Type I hypersensitivity disorders, such as asthma, hay fever, and atopic eczema, are stimulated by binding to Azp-receptors of mast cells. Therefore, blocking these adenosine receptors would provide a therapeutic benefit against such disorders. "There are several compounds presently used in the treatment of asthma. For example, theophylline is an effective antiasthmatic agent, even though it is a poor adenosine receptor antagonist. However, considerable plasma levels are needed for it to be effective. Additionally, theophylline has substantial side effects, most of which are due to its CNS action, which provide no beneficial effects in asthma, and to the fact that it non-specifically blocks all adenosine receptor subtypes.
Additionally adenosine treatment, such as inhaled adenosine (or adenosine monophosphate), provokes bronchoconstriction in asthmatics, but not in the normal population. This process is known to involve mast cell activation, in that it releases mast cell mediators, including histamine, PGD2- B-hexosaminidase and tryptase, and because it can be blocked by specific histamine H; blockers and chromolyn sodium.
Accordingly, there is an intrinsic difference in the way adenosine interacts with mast cells from asthmatics, and thus A,p antagonists are particularly useful in modulating mast cell function or in the activation of human lung cells.
Accordingly, it is desired to provide compounds that are potent Ap antagonists (i.e., compounds that inhibit the Ayp adenosine receptor), fully or partially selective for the Ap receptor, useful in the treatment of various disease states related to modulation of the Ap receptor, for example cancer, asthma and diarrhea.
SUMMARY OF THE INVENTION
U.S. Non-Provisional Patent Application Serial No. 10/431,167 discloses novel A,p adenosine receptor antagonists
A category of preferred compounds that fall within the scope of this invention has been identified. Preferred compounds of Formula I include those in which R! and
R? are independently optionally substituted lower alkyl, especially those compounds in which R! and R? are different, and are lower alkyl optionally substituted by cycloalkyl. More preferred are those compounds in which X is pyrazol-4-yl, Y is methylene, and Z is optionally substituted phenyl, especially phenyl substituted with trifluoromethyl. Even more preferred are those compounds in which R! and R? are chosen from ethyl, n-propyl cyclopropylmethyl, or iso-butyl, especially those in which R! is n-propyl and R? is ethyl. A preferred Z is 3-trifluoromethylphenyl.
Consequently, novel processes for the preparation of such compounds have been developed.
Accordingly, in a first aspect, the invention relates to a process for the preparation of a compound of the formula: o)
AN 9s
A\
PY | Hv ) N N k
Formula I wherein:
R! and R? are independently optionally substituted alkyl;
X is optionally substituted arylene or optionally substituted heteroarylene;
Y is a covalent bond or lower alkylene; and
Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; comprising; contacting a compound of the formula : fo rR. AY SNP ’ ~N
JL
0) N NH; ; . 3 in which R}, R% X,Y, and Z are as defined above; with a base.
In a preferred embodiment, the compound of formula (3) is contacted with a base, preferably in a protic solvent. The base is preferably chosen from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and potassium t-butoxide preferably aqueous sodium hydroxide solution, and the protic solvent is preferably methanol.
Tn a second aspect, the invention relates to a process for the preparation of a compound of formula (3): 0
AR. 84 NL
N ~N
JA o N NH, \ €)) in which R!, R?, X, Y and Z are as defined above; comprising: contacting a compound of the formula (2); 0
AN oy
A NH, lL @
with a carboxylic acid of the formula Z-Y-X-CO,H, in which X, Y and Z are as defined above.
In a preferred embodiment, the compound of formula (2) is contacted with a compound of the formula Z-Y-X-CO,H in a polar solvent, preferably methanol, in the presence of a coupling agent used to form amide bonds, preferably a carbodiimide derivative. In a more preferred embodiment the carbodiimide derivative is 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide. Alternatively, the compound of formula (2) is contacted with an acid halide of the formula Z-Y-X-C(O)L, where L is chloro or bromo.
In a third aspect, the invention relates to a process for the preparation ofa compound of formula (3): 0
RS 86 AN
N ~ Y
ANS fo N NH, kL 3) in which R!, R?, X, Y and Z are as defined above; comprising: contacting a compound of the formula (16); 0 “ SOB
PS lo) N NH, k (16) in which R%, X, Y and Z are as defined above; with a compound of the formula R'L, in which L is a leaving group.
In a preferred embodiment, the compound of formula (16) is contacted with an alkyl halide, preferably an alkyl iodide, in the presence of a base, preferably potassium carbonate, in a polar solvent, preferably N,N-dimethylformamide.
In a fourth aspect, the invention relates to a process for the preparation of a compound of formula (3):
0
AN 86 Xe? . NO
JX! o N NH, © in which R}, R%, X,Y and Z are as defined above; comprising: contacting a compound of formula (13) 0
NG YS Pr:
LL] o@ ON NH, ! (13) in which R}, X, Y and Z are as defined above; with a compound of the formula RL, in which L is a leaving group.
In a preferred embodiment, the compound of formula (13) is contacted with an alkyl halide, preferably an alkyl iodide, in the presence of a base, preferably potassium carbonate, in a polar solvent, preferably N,N-dimethylformamide.
In a fifth aspect, the invention relates to a process for the preparation of a compound of formula (16): 0
POG BS
AS lo) N NH; k i5 (16) in which R%, X, Y and Z are as defined above; comprising: contacting a compound of formula (15):
0 ’Oe
A, NH, . (15) in which R? is as defined above; with a carboxylic acid of the formula Z-Y-X-CO,H; in which X, Y and Z are as defined above.
In a preferred embodiment, the compound of formula (15) is contacted with a compound of the formula Z-Y-X-COH in a polar solvent, preferably methanol, in the presence of a coupling agent used to form amide bonds, preferably a carbodiimide derivative. In a more preferred embodiment the carbodiimide derivative is 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide. Alternatively, the compound of formula (15) is contacted with an acid halide of the formula Z-Y-X-C(O)L, where L is chloro or bromo.
In a sixth aspect, the invention relates to a process for the preparation of a compound of formula (13): fo)
TY
JC
0 N NH, } (13) in which R!, X, Y and Z are as defined above; comprising: contacting a compound of formula (12)
Q
TY
AP
(12) in which R! is as defined above; with a carboxylic acid of the formula Z-Y-X-CO,H; in which X, Y and Z are as defined above.
In a preferred embodiment, the compound of formula (12) is contacted with a compound of the formula Z-Y-X-CO,H in a polar solvent, preferably methanol, in the presence of a coupling agent used to form amide bonds, preferably a carbodiimide derivative. In a more preferred embodiment the carbodiimide derivative is 1-(3- dimethylaminopropyl)-3-ethyicarbodiimide. Alternatively, the compound of formula (12) is contacted with an acid halide of the formula Z-Y-X-C(O)L, where L is chloro or bromo.
In a seventh aspect, the invention relates to a process for the preparation of a compound of formula (15): o)
A k (15) in which R? is as defined above; comprising the steps of: 1) contacting a compound of formula (4):
AN
NH en
C)) with ethyl cyanoacetate in the presence of a base in a protic solvent, preferably ethanoV/sodium ethoxide; 2) contacting the product thus formed:
[0]
J. : R? (5) with a mixture of sodium nitrite in acetic acid/water; and 3) contacting the product thus formed: [o} ed 1 1
JX.
Rr2 (14) with a mixture of aqueous ammonia and sodium dithionite.
In an eighth aspect, the invention relates to a process for the preparation of a compound of formula (12): 0) \] NH,
TX
A NH,
H
(12) in which R! is as defined above; comprising the steps of: 1 contacting a compound of the formula: fo
PN NH, with a) hexamethyldisilazane followed by b) R'L, where R! is as defined above and L is a leaving group;
2) contacting the compound thus formed:
[0]
PN N NH, (10) with a mixture of sodium nitrite in acetic acid/water; and 3) contacting the product thus formed: 0
R! NO ~ N YX
AP
(11) with a mixture of aqueous ammonia and sodium dithionite.
In a ninth aspect, the invention relates to a process for the preparation of a compound of formula (2): 0 1 NH,
TY
A NH,
R2 2) in which R! and R? are as defined above; comprising the steps of: 1) contacting a compound of the formula: 2
RS NH
- 4) with ethyl cyanoacetate in the presence of a base in a protic solvent, preferably ethanol/sodium ethoxide; 2) contacting the product thus formed:
0 . HN N
PON
R? &)) with the dimethylacetal of N,N-dimethylformamide; 3) contacting the product thus formed:
[0] oN ~~
PN | = re ® with a compound of formula R'L, in which L is a leaving group, preferably an iodide, in the presence of a base, preferably potassium carbonate, in a polar solvent, preferably N,N-dimethylformamide. 4) contacting the product thus formed: 0
R},
Sn | Ny r = rR
OQ) with aqueous ammonia; 5) contacting the product thus formed:
[9]
PQ
A NH,
Re : ® with a mixture of sodium nitrite in acetic acid/water; and 6) contacting the product thus formed:
[o]
Rr!
A, NH;
R2 1) with a mixture of aqueous ammonia and sodium dithionite.
In a tenth aspect, the invention relates to a process for the preparation of a compound of formula (7)
[0]
R'
N | ~~
EN | =
RZ
¢)] comprising the steps of: 1 contacting a compound of the formula: ol
R!
TI
[o} N NH, 10) with the dimethylacetal of N,N-dimethylformamide; 2) contacting the product thus formed:
[0] rR? 1. J
AN J with a compound of formula RL, in which L is a leaving group, preferably an iodide, in the presence of a base, preferably potassium carbonate, in a polar solvent, preferably N,N-dimethylformamide; and 3) contacting the product thus formed:
[o}
TO or
A N = \ with aqueous ammonia.
In an eleventh aspect, the invention relates to a novel intermediate of the formula: [o]
TL
A ad
R2 in which R! is n-propyl, 2-methylpropyl, or cyclopropylmethyl and R? is methyl or ethyl.
Particularly preferred is the compound in which R! is n-propyl and R? is ethyl:
A nd § namely 6-[2-(dimethylamino)-1-azavinyl]-1-ethyl-3-propyl-1,3-dihydropyrimidine- 2,4-dione.
In a twelfth aspect, the invention relates to a novel intermediate of the formula: [o} =
RY
OT
PN v
Fy in which R! is n-propyl or cyclopropylmethyl, preferably n-propyl
0 =
ING NY VY
PP. o N NH,
FsC namely N-(6-amino-2,4-dioxo-3-propyl(1,3-dihydropyrimidin-5-y))(1-{[3- (triftuoromethyl)-phenyl]methyl}pyrazol-4-yl)carboxamide.
In a thirteenth aspect, the invention relates to a novel intermediate of the formula:
N
0 — \,
NH =.
HN
ANS o N NH, l, FiC in which R? is methyl or ethyl, preferably ethyl; 2
N
NH ==
HN
AA o N NH, § FaC namely N-(6-amino-1-ethyl-2,4-dioxo(1,3-dihydropyrimidin-5-yI))(1-{[3- (trifluoromethyl)phenyl]methyl} pyrazol-4-yl)carboxamide;
In a fourteenth aspect, the invention relates to a novel intermediate of the formula:
N
[eo] — \ rR!
Nu a ES
ANS oO N NH, lL, F\C in which R! is n-propyl, 2-methylpropyl, or cyclopropylmethyl and R? is methyl or ethyl.
Particularly preferred is the intermediate in which R! is n-propyl and R? is ethyl; 0 | DO
SN Za eR lo] N NH, fe § FaC namely N-(6-amino-1-ethyl-2,4-dioxo-3-propyl(1,3 -dihydropyrimidin-5-yI))(1-{[3- (trifluoromethyl)phenyljmethyl} pyrazol-4-yl)carboxamide.
Other aspects of the invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of a compound of Formula I and at least one pharmaceutically acceptable excipient.
A further aspect of this invention relates to a method of using the compounds of Formula I in the treatment of a disease or condition in a mammal that is treatable by inhibiting an adenosine receptor characterized as Ass, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula
I Such diseases include, but are not limited to, at least one of asthma, inflammatory gastrointestinal tract disorders, including diarrhea, cardiovascular diseases such as atherosclerosis, neurological disorders such as senile dementia, Alzheimer’s disease, and Parkinson’s disease, and diseases related to angiogenesis, for example diabetic retinopathy and cancer.
One preferred group of compounds of Formula I are those in which R! and R? are different and are independently lower alkyl optionally substituted by cycloalkyl.
Within this group, a first preferred class of compounds include those in which R! is lower alkyl of 2-4 carbon atoms optionally substituted by cyclopropyl and R? is lower alkyl of 2-4 carbon atoms, particularly where R! and R? are chosen from ethyl and n- propyl, and X is optionally substituted pyrazolen-1,4-yl. Within this class, a preferred subclass of compounds is where Y is lower alkylene, preferably methylene, and Z is optionally substituted phenyl, preferably 3-trifluoromethylphenyl. Most preferred are those compounds of Formula I in which R! is n-propyl and R? is ethyl.
At present, the preferred compounds are: 3-ethyl-1-propyl-8-(1-{[3-(trifluoromethyl)phenyljmethyl} pyrazol-4-yl)-1,3,7- trihydropurine-2,6-dione;
1-cyclopropylmethyl-3-methyl-8-[1-(phenylmethyl)pyrazol-4-yi}-1,3,7- trihydropurine-2,6-dione; 1-cyclopropylmethyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}- " 1,3,7-trihydropurine-2,6-dione; l-cyclopropylmethyl-3-ethyl-8- {1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}- 1,3,7-trihydropurine-2,6-dione; 1-cyclopropylmethyl-3-methyl-8- {1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7- trihydropurine-2,6-dione; 1-cyclopropylmethyl-3-ethyl-8- {1-[(3-fluorophenyl)methyl]pyrazol-4-y1}-1,3,7- 1¢ trihydropurine-2,6-dione; 1-cyclopropylmethyl-3-ethyl-8-(1- {[6-(trifluoromethyl)(3 -pyridyl)lmethyl}pyrazol-4- y1)-1,3,7-trihydropurine-2,6-dione; : 3-({4-[1-(cyclopropylmethyl)-3-methyl-2,6-dioxo-1,3,7-trihydropurin-8- yl]pyrazolyl}methyl)benzenecarbonitrile; 8-[1-(2-(1H-1,2,3,4-tetraazol-5-yl)ethyl)pyrazol-4-yl]-3-methyl-1-cyclopropylmethyl- 1,3,7-trihydropurine-2,6-dione; : 1-(2-methylpropyl)-3-methyl-8-[ 1-benzylpyrazol-4-yi]-1,3,7-trihydropurine-2,6- dione; 1-(2-methylpropyl)-3-ethyl-8- {1-[(3-fluorophenyl)methylipyrazol-4-yl}-1,3,7- trihydropurine-2,6-dione; 1-(2-methylpropyl)-3-methyl-8- {1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl }- 1,3,7-trihydropurine-2,6-dione; 1-(2-methylpropyl)-3-methyl-8- {1-[(3-fluorophenyl)methyl]pyrazol-4-y1}-1,3,7- trihydropurine-2,6-dione; 3-ethyl-1-(2-methylpropyl)-8-(1- {[6-(trifluoromethyl)(3-pyridyl)Jmethyl} pyrazol-4- yl)-1,3,7-trihydropurine-2,6-dione; 1-ethyl-3-methyl-8- {1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine- 2,6-dione; and 3-ethyl-1-propyl-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.
Particularly preferred is 3-ethyl-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]- methyl} pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
Definitions and General Parameters
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
The term “alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1,2, 3, 4, 5, 6, 7,8,9,10, 11, 12, 13, 14,15, 16, 17, 18, 19 or 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, p-decyl, tetradecyl, and the like.
The term “substituted alkyl” refers to: 1) an alkyl group as defined above, having 1,2, 3,4 or 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SOz-alkyl, SO;-aryl and -SO,- heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and —S(O),R, where R is alkyl, aryl, or heteroaryl andn is 0, 1 or 2; or 2) an alkyl group as defined above that is interrupted by 1-10 atoms independently chosen from oxygen, sulfur and NR,-, where Rg is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CFs, amino, substituted amino, cyano, or ~S(O)R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2; or 3) an alkyl group as defined above that has both 1, 2, 3,4 or 5 substituents as defined above and is also interrupted by 1-10 atoms as defined above.
The term “lower alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.
The term “substituted lower alkyl” refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1, 2, or 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1,2, 3,4, 0r 5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined above.
The term “alkylene” refers to a diradical of a branched or unbranched ‘saturated hydrocarbon chain, having 1,2,3,4,5,6,7,8,9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups such as methylene (-CHy-), ethylene (-CH,CH3-), the propylene isomers (e.g., -CH2CH,CHz- and-CH(CH3)CH;-) and the like.
The term “lower alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms.
The term “lower alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms.
The term*“substituted alkylene” refers to: : (1) an alkylene group as defined above having 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO2-alkyl, SOz-aryl and -SO-- heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CFs, amino, substituted amino, cyano, and ~S(O).R, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2; or (2) an alkylene group as defined above that is interrupted by 1-20atoms independently chosen from oxygen, sulfur and NR,-, where Ra is chosen from

Claims (55)

  1. WHAT IS CLAIMED IS: L A process for the preparation of a compound of Formula I: 0 l] R PY Hv fo) \ N R2 Formula I wherein: R' and R? are independently optionally substituted alkyl; X is optionally substituted arylene or optionally substituted heteroarylene; Y is a covalent bond or lower alkylene; and Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl, comprising; cyclizing a compound of the formula (3): o) RAC R XE i YOY ANS Co \ NH, Rr? &)] wherein R', R%L X, Y, and Z are as defined above.
  2. 2. The process of claim 1, wherein the compound of formula (3) is cyclized in an inert solvent in the presence of a base.
  3. 3. The process of claim 2, wherein the inert solvent is methanol and the base is aqueous sodium hydroxide solution.
  4. 4, The process of claim 3, wherein R' and R? are independently lower alkyl, X is pyrazol-4-yl, Y is methylene, and Z is optionally substituted phenyl.
  5. 5. The process of claim 4, wherein R' is n-propyl, R? is ethyl, and Z is 3- trifluoromethylphenyl.
  6. 6. The process of claim 1, wherein the compound of formula (3): 0 RS Ny ot N Y AN 0 N NH, : R2 3 is prepared by a method comprising contacting a compound of the formula (2); O 14 NH; : “TY A NH, Re @ with a compound of the formula 7.¥-X-CO;H or Z-Y-X-C(O)Hal, where Hal is \ chloro or bromo.
  7. 7. The process of claim 6, wherein the compound of formula (3) is reacted with Z-Y-X-CO,H in methanol in the presence of a coupling agent used to form amide bonds. :
  8. 8. The process of claim 7, wherein the coupling agent used to form amide bonds is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  9. 9. The process of claim 6, wherein the compound of formula (3) is reacted with Z-Y-X-C(O)CL
  10. 10. The process of claim 9, wherein the reaction is carried out in an inert solvent in the presence of a tertiary base.
  11. 11. The process of claim 10, wherein the inert solvent is acetonitrile and the tertiary base is triethylamine.
  12. 12. The process of claim 6, wherein R' and R? are independently lower alkyl, X is pyrazol-4-yl, Y is methylene, and Z is optionally substituted phenyl.
  13. 13. The process of claim 12, wherein R! is n-propyl, R? is ethyl, and Z is 3- trifluoromethylphenyl, namely 3-ethyl-1-propyl-8-{1-[(3- trifluoromethylphenyl)methyl]pyrazol-4-yi}-1,3 ,7-trihydropurine-2,6-dione.
  14. 14. The process of claim1, wherein the compound of the formula: 0 RAL R Xo z N ~ v ANS 0 \ NH, R? 3) is prepared by a method comprising contacting a compound of the formula; 0 d X z GaN ~ ~~ A o \ NH; R2 (16) with a compound of the formula R'L, in which L is a leaving group.
  15. 15. The process of claim 14, wherein R! is lower alkyl optionally substituted by cycloalkyl, and L is iodo.
  16. 16. The process of claim 15, wherein the reaction is carried out in the presence of a base in an inert solvent.
  17. 17. The process of claim 16, wherein the base is potassium carbonate and the inert solvent is N,N-dimethylformamide.
  18. 18. The process of claim 17, wherein R' and R* are independently lower alkyl, X is pyrazol-4-yl, Y is methylene, and Zis optionally substituted phenyl.
  19. 19. The process of claim 18, wherein R! is n-propyl, R? is ethyl, and Z is 3- trifluoromethylphenyl.
  20. 20. The process of claim], wherein the compound of the formula: fo RL x 2 N Y PR p ’ oO | NH; R2 3) is prepared by a method comprising contacting a compound of the formula; 0 RL NS Zz N Y PY 0 lo) \ NH, H (13) with a compound of the formula RL, in which L is a leaving group.
  21. 21. The process of claim 20, wherein R? is lower alkyl optionally substituted by cycloalkyl, and L is iodo.
  22. 22. The process of claim 21, wherein the reaction is carried out in the presence of a base in an inert solvent.
  23. 23. The process of claim 22, wherein the base is potassium carbonate and the inert solvent is N,N-dimethylformamide.
  24. 24. The process of claim 23, wherein R' and R? are independently lower alkyl, X is pyrazol-4-yl, Y is methylene, and Z is optionally substituted phenyl.
  25. 25. The process of claim 24, wherein R! is n-propyl, R? is ethyl, and Z is 3- trifluoromethylphenyl.
  26. 26. The process of claim 14, wherein the compound of the formula: lo HN N I~ N Y 1 Y i o \ NH RR (16) is prepared by a method comprising contacting a compound of the formula: 0 NH, Y PN NH, I (15) with a compound of the formula Z-Y-X-CO,H or Z-Y-X-C(O)Hal, where Hal is chloro or bromo.
  27. 27. The process of claim 26, wherein the compound of formula (15) is reacted with Z-Y-X-CO,H in methanol in the presence of a coupling agent used to form amide bonds.
  28. 28. The process of claim 27, wherein the coupling agent used to form amide bonds is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  29. 29. The process of claim 26, wherein the compound of formula (15) is reacted with Z-Y-X-C(O)CL
  30. 30. The process of claim 29, wherein the reaction is carried out in an inert solvent in the presence of a tertiary base.
  31. 31. The process of claim 30, wherein the inert solvent is acetonitrile and the tertiary base is triethylamine.
  32. 32. The process of claim 31, wherein R! and R? are independently lower alkyl, X is pyrazol-4-yl, Y is methylene, andZis optionally substituted phenyl.
  33. 33. The process of claim 32, wherein R! is n-propyl, R?is ethyl, and Z is 3- trifluoromethylphenyl.
  34. 34. The process of claim 19, wherein the compound of the formula: 0 RL y Xo Pe: ) YO AN lo) | NH H 13) is prepared by a method comprising contacting a compound of the formula: Q 1 NH, TY A NH, H (12)
    with a compound of the formula Z-Y-X-CO.H or Z-Y-X-C(O)Hal, where Hal is chloro or bromo.
  35. 35. The process of claim 34, wherein the compound of formula (12) is reacted with Z-Y-X-CO,H in methanol in the presence of a coupling agent used to form amide bonds.
  36. 36. The process of claim 35, wherein the coupling agent used to form amide bonds is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  37. 37. The process of claim 34, wherein the compound of formula (12) is reacted with Z-Y-X-C(O)CL
  38. 38. The process of claim 37, wherein the reaction is carried out in an inert solvent inthe presence of a tertiary base.
  39. 39. The process of claim 38, wherein the inert solvent is acetonitrile and the tertiary base is triethylamine.
  40. 40. The process of claim 39, wherein R! and R? are independently lower alkyl, X is pyrazol-4-yl, Y is methylene, and Z is optionally substituted phenyl.
  41. 41. The process of claim 40, wherein R! is n-propyl, R? is ethyl, and Z is 3- trifluoromethylphenyl. 42, The process of claim 34, wherein the compound of the formula: fo) x NH, TY A NH, H 12) is prepared by a method comprising the steps of: a) contacting a compound of the formula:
  42. : 0 A NH, with hexamethyldisilazane in the presence of an acid catalyst; b) contacting the product thus formed with R'L, where L is a leaving group, followed by; ¢ contacting the product thus formed: [o} R! yo A NH, (10) with a mixture of sodium nitrite in acetic acid/water; and d) contacting the product thus formed: 0 R’ NO A, NH (11) with a mixture of aqueous ammonia and sodium dithionite.
  43. 43. The process of claim 42, wherein in step a) R! is lower alkyl, L is iodo, and the acid catalyst is ammonium sulfate.
  44. 44. The process of claim 26, wherein the compound of the formula: Io} NH,
    IY . A NH, rR? (15) is prepared by a method comprising the steps of:
    a) contacting a compound of the formula: R2 SH A with ethyl cyanoacetate in the presence of a base in a protic solvent; b) contacting the product thus formed: [o] A NH, R? with a mixture of sodium nitrite in acetic acid/water; and c) contacting the product thus formed: [o} 94 HN A NH, Rr? with a mixture of aqueous ammonia and sodium dithionite.
  45. 45. The process of claim 44, wherein the base is sodium ethoxide and the protic solvent is ethanol.
  46. 46. The process of claim 6, wherein the compound of formula: 0 1 NH Ny Y 2 A NH, R? @ is prepared by a method comprising the steps of: a) contacting a compound of the formula:
    RS NH PN, “) with ethyl cyanoacetate in the presence of a base in a protic solvent; b) contacting the product thus formed: 0 A NH, rR? with the dimethylacetal of N,N-dimethylformamide; c) contacting the product thus formed: [o] el ~N A = rR? with a compound of formula R'L, in which L is a leaving group; d) contacting the product thus formed:
    [8] Ri! ) 1, J A | = Re with aqueous ammonia; €) contacting the product thus formed: 0 rR. ~~ A A NH; rR? with a mixture of sodium nitrite in acetic acid/water; and 6) contacting the product thus formed:
    [0] ped A, NH, R2 with a mixture of aqueous ammonia and sodium dithionite.
  47. 47. The process of claim 46, wherein the base is sodium ethoxide and the protic solvent is ethanol.
  48. 48. An intermediate of the formula: 0 RI TL PY aad rR? wherein: Rand R? are independently chosen from methyl, ethyl, n-propyl, 2-methylpropyl, and cyclopropylmethyl.
  49. 49. The intermediate of claim 48, wherein R' is n-propyl and R; is ethyl: [e] ry 06 > namely 6-[2-(dimethylamino)-1-azavinyl]-1-ethyl-3-propyl-1 ,3-dihydropyrimidine-
    2.4-dione.
  50. 50. An intermediate of the formula:
    [0] = NG NH Sg N N AN lo) N NH, FaC wherein R! is n-propyl or cyclopropylmethyl.
  51. 51. The intermediate of claim 50, wherein R' is n-propyl: [o] = STN ye ANS o N NH, FaC namely N-(6-amino-2,4-dioxo-3-propyl(1,3 -dihydropyrimidin-5-y1))(1-{[3- (trifluoromethyl)-phenyl)methyl} pyrazol-4-ylcarbox amide. 52 An intermediate of the formula: N
  52. [0] — \ NH = HN ANS 0 N NH, lL FaC wherein R? is methyl or ethyl.
  53. 53. The intermediate of claim 52, wherein R? is ethyl: N [o] el \ NH = HN ANS 0 N NH,
    § . (19) N-(6-amino-1-ethyl-2,4-dioxo(1,3-dihydropyrimidin-5-y))(1-{[3- (trifluoromethyl)phenyljmethyl} pyrazol-4-yt)carboxamide.
  54. 54 An intermediate of the formula: R! N NY NH x PY | ° 0 N NH, i ” wherein R' and R? are independently chosen from methyl, ethyl, n-propyl, 2- methylpropyl, and cyclopropylmethyl.
  55. 55 The intermediate of claim 54 wherein R' is n-propyl and R; is ethyl: N — \, Nn NH J ANS 0 N NH, § ; namely N-(6-amino-1-ethyl-2,4-dioxo-3-propyl(1,3-dihydropyrimidin-5-y1))(1- {[3- (trifluoromethyl)phenylimethyl} pyrazol-4-yl)carboxamide.
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